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All sorts of disparate functions in higher animals have evolved to influence one another. In part this is because evolution produces promiscuous reuse of component parts, so any one given gene or the protein it encodes may have numerous functions and impact numerous different biological systems. Coupled with the fact that there are an awful lot of proteins making up our cellular machinery, this means that any attempt to alter the operation of metabolism so as to reliably and safely slow aging and extend healthy life is a challenging prospect. Researchers have spent a few billion of dollars and more than a decade simply trying to recreate the known and well-researched enhancements to health and longevity produced by calorie restriction. There is no available therapy to show for this work as of yet, and it is clear that there remains a fair way to go to reach even a good, comprehensive, and defensible model of how this one single type of metabolic alteration works. It is a ferociously complex business.

Then there are many other normally hidden linkages between, on the one hand, parts of metabolism that have nothing to do with longevity and, on the other hand, parts that do in fact influence both aging and health. These relationships do not tend to come into play in nature in the same dramatic manner as the metabolic shift brought on by calorie restriction - otherwise they wouldn't be hidden. But when you have a laboratory and modern biotechnology, all sorts of sometimes surprising connections can be uncovered. Take this connection between a component of pain sensing and insulin metabolism, for example:

Mice lacking the pain receptor TRPV1 live longer than controls and have more youthful metabolisms. While searching for an explanation for the mutant rodents' longevity, the researchers discovered that the animals responded to glucose extraordinarily efficiently even once they reached advanced age. Young mice with healthy metabolisms rapidly clear glucose from their blood streams, while it tends to linger in older mice with metabolic disorders. The mice without TRPV1 were able to produce spikes in insulin and to clear the glucose throughout their lives, whereas the control mice were less able to ramp up insulin production to clear glucose as they aged.

Curious about how TRPV1 influences insulin production, the researchers switched to another model organism: Caenorhabditis elegans. When C. elegans lost the worm equivalents of TRPV1, the mutant worms lived up to 32 percent longer than did controls.

Through experiments in both C. elegans and mice, the researchers found that overactive TRPV1 reduces longevity through setting off a calcium-signaling cascade. In mice, this eventually leads to over-production of the neuropeptide CGRP in sensory neurons that innervate the pancreas. The presence of CGRP in these neurons suppresses insulin secretion. As a final test, the researchers blocked CGRP in elderly wild-type mice. Following sustained treatment, the animals' metabolic functions began to resemble those of younger mice. [Researchers] hypothesized that TRPV1 is overactive in older mice due to chronic inflammation, which is known to activate the pain receptor and is a hallmark of type 2 diabetes.

The sensation of pain is associated with increased mortality, but it is unknown whether pain perception can directly affect aging. We find that mice lacking TRPV1 pain receptors are long-lived, displaying a youthful metabolic profile at old age. Loss of TRPV1 inactivates a calcium-signaling cascade that ends in the nuclear exclusion of the CREB-regulated transcriptional coactivator CRTC1 within pain sensory neurons originating from the spinal cord. In long-lived TRPV1 knockout mice, CRTC1 nuclear exclusion decreases production of the neuropeptide CGRP from sensory endings innervating the pancreatic islets, subsequently promoting insulin secretion and metabolic health.

In contrast, CGRP homeostasis is disrupted with age in wild-type mice, resulting in metabolic decline. We show that pharmacologic inactivation of CGRP receptors in old wild-type animals can restore metabolic health. These data suggest that ablation of select pain sensory receptors or the inhibition of CGRP are associated with increased metabolic health and control longevity.

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